Summary Obesity increases morbidity and resource utilization of critically ill including sepsis; sepsis, the most expensive condition in the US, is the leading cause of death in critically ill patients. The early hyper-inflammatory response of sepsis quickly transitions to hypo-inflammatory and immunosuppressive phase. Most patients die during the immunosuppressive phase of late sepsis, because they cannot clear infections. We have shown previously, that the lean (C57Bl/6 wild type: WT) mice and their monocytes undergo an early/hyper-inflammatory (endotoxin responsive), late/hypo-inflammatory (endotoxin tolerant) and resolution (return of endotoxin response) phases, however, in leptin deficient-obese ob/ob mice, we found that the hyper- inflammatory phase transitioned quickly to a prolonged hypo-inflammatory phase and that survival was decreased compared to lean mice. The transition from the hyper- to hypo-inflammatory phase is accompanied by profound changes in monocyte metabolism in mice and obese-sepsis patients; monocytes depend on glycolysis energy during the hyper- but fatty acid oxidation during the hypo-inflammatory phase. The switch from glycolytic/hyper- to fatty acid-dependent/hypo-inflammation is controlled by the NAD+ sensor sirtuin (SIRT) family of proteins (SIRTs 1-7). Earlier we showed that in lean/WT mice, increased SIRT1 controls the switch from hyper- to hypo-inflammation; SIRT1 inhibition during hypo-inflammation improves survival. In ob/ob mice, increased SIRT2 expression controls the switch and prolongs the hypo-inflammation; SIRT2 inhibition during hypo-inflammation reverses the endotoxin tolerance and improves survival. In contrast to our findings in lean mice, we found that the SIRT1 inhibition during the hypo-inflammatory phase of ob/ob- sepsis decreased survival. Thus our published and preliminary data support an obesity-specific role for SIRT2. In this proposal, we will elucidate the role of SIRT2 in modulation of immuno-metabolic responses in clinically relevant, leptin resistant nutritionally obese (diet induced obese: DIO) mice with sepsis. This proposal?s general working hypothesis is that SIRT2 a critical regulator of immuno-metabolic responses in diet-induced obesity with sepsis. We propose two Specific Aims, designed to develop this new concept. Aim 1 will define the role of SIRT2 in regulating immuno-metabolic responses in obesity with sepsis, using genetic and pharmacological modification of SIRT2 in lean and obese mice during early vs. late sepsis. Aim 2 will determine how SIRT2 protein levels and function themselves are regulated in obesity with sepsis. Impact: Completing these aims will deepen our understanding of how obesity alters immuno- metabolic properties of sepsis-inflammation. Sepsis, the most expensive condition in the US kills >200,000 people each year. A better understanding of how obesity and sepsis interact could shorten the hypo-inflammatory phase, thereby having a marked impact on morbidity, mortality, and costs associated with sepsis.